PROJECT SUMMARY This is an emergency competitive revision to our existing R01 AI121129. As part of this parent R01 entitled, ?Immunoprotective properties of tissue-resident memory T cells in mice and humans within mucosal sites?, we perform longitudinal sampling of the genital skin and HSV-2 lesions for both viral load as well as cytokine levels. This approach was highlighted in our recent paper in the Journal of Clinical Investigation (Roychoudhury et al, 2020, PMID 32125285), in which we show that T cell-derived proteins including interferon gamma and granzyme B surge concurrently with local viral load. We now propose to use this successful approach to a second infectious disease, SARS-CoV-2. The COVID-19 pandemic is an unprecedented event in modern human history, with morbidity and mortality rates dangerously high in the elderly and those with medical comorbidities. Given the current pandemic status, the most urgent goal is to lower case fatality and hospitalization rates. Front line providers need reliable tests to rapidly triage infected patients according to severity and effective therapies to treat them. There is reason for hope; the mean time between presentation and need for hospitalization is a week for SARS-CoV-2 infected patients, which allows a much longer window to intervene than for influenza infection; clinical trials are already assessing various small molecular agents and neutralizing antibodies. Thus, the goals of this application are to use an existing prospective cohort to assess multiple potential biomarkers of progression to severe disease at initial clinical presentation, identify immunologic variables associated with viral elimination over ensuing weeks, and model the optimal timing, dose and duration of therapeutic interventions to prevent respiratory failure. We will leverage the currently surging local epidemic in Seattle; an IRB-approved protocol which is already enrolling infected outpatient participants; a wide network of referring providers; and our multi-disciplinary team of clinicians, T-cell immunologists, and mathematical modelers, who have existing, complementary tools and existing collaborations, to rapidly produce and analyze critical data. We will share our results openly and in real time with the international scientific community to assist in managing this global emergency.